ABSTRACT
Acquired haemophilia A (AHA) is a rare disorder with an incidence of 1.5 cases per million per year in the United Kingdom. The incidence could be underestimated due to difficulty in diagnosis and also due to the fact that people with low titre inhibitor levels are asymptomatic. It is usually a disease affecting elderly but a disease peak in the younger population is known. The common underlying diseases are autoimmune disorders, malignancies, infections, and drugs. However, approximately 50% of the cases do not have a specific aetiology and about 10% will not have bleeding manifestations. Therefore, an isolated prolongation of APTT should be evaluated, especially prior to any haemostatic challenges. We report a case of a middle-aged man who presented with bleeding due to AHA associated with high inhibitory titres and active pulmonary tuberculosis. He was treated with both antituberculous and combined-aggressive immunosuppressive therapy which resulted in satisfactory disease remission.
ABSTRACT
DACA [N-[2-(dimethylamino)ethyl]acridine-4-carboxamide] is an acridine derivative with high activity against solid tumours in mice and a dual mode of cytotoxic action involving topoisomerases I and II. The plasma pharmacokinetics of DACA were studied in 28 patients with solid tumours in a phase I trial. A single dose was given every 3 weeks, being escalated from a starting dose of 18 mg/m2 (as the dihydrochloride trihydrate salt) to a maximal dose, limited by severe pain in the infusion arm, of 1000 mg/m2. Drug was given by constant intravenous infusion with a target delivery period of 3 h. Blood samples were taken from the contralateral arm before, during and for up to 72 h after the infusion. DACA was separated from plasma by solid-phase extraction and was analysed by reversed-phase high-performance liquid chromatography (C18 column) using fluorescence detection. A two-compartment pharmacokinetic model provided the best fit for the concentration-time profiles obtained for most patients showing clearance of 1.00+/-0.36 l h(-1) kg(-1), a volume of distribution of the central compartment of 0.72+/-0.55 l/kg, an initial half-life of 0.28+/-0.19 h and a terminal half-life of 2.04+/-0.94 h. All pharmacokinetic parameters were independent of dose, indicating first-order kinetics. As DACA binds strongly to alpha1-acid glycoprotein, plasma concentrations of this protein were determined and used to estimate free-drug fractions in plasma. Estimated values for the free fraction varied from 0.9% to 3.3% and were lower than those determined by equilibrium dialysis for mice and rats (15% and 16%, respectively). At the maximum tolerated dose (MTD) of 750 mg/m2, the area under the drug concentration-time curve (AUC) was 46.2+/-4.4 microM h, exceeding that obtained in mice treated at the MTD (23.4 microM h). On the other hand, the corresponding free-drug AUC was 0.92+/-0.03 microM h, much lower than the corresponding value (3.5 microM h) determined for mice. These results suggest that free-drug rather than total drug concentrations are more appropriate for interspecies dose comparisons when significant differences exist in the free plasma fraction.
Subject(s)
Acridines/pharmacokinetics , Antineoplastic Agents/pharmacokinetics , Acridines/administration & dosage , Adult , Aged , Antineoplastic Agents/administration & dosage , Area Under Curve , Dose-Response Relationship, Drug , Female , Half-Life , Humans , Infusions, Intravenous , Male , Middle Aged , Neoplasms/drug therapy , Neoplasms/metabolismABSTRACT
Several drugs with structural similarities to SKF-525A were tested for their ability to inhibit rat liver aldehyde oxidase using the experimental antitumour agent N-[(2'-dimethylamino)ethyl]acridine-4-carboxamide (AC; NSC 601316; acridine carboxamide) as substrate. The antihistamine D-chlorpheniramine, and the antiarrhythmics disopyramide, procainamide and lignocaine were ineffective in inhibiting this reaction. The antihistamines diphenhydramine, pheniramine, doxylamine, orphenadrine, methapyrilene and pyrilamine, gave IC50 values of 100-500 microM. The narcotic analgesics D-propoxyphene and, in particular, methadone were potent inhibitors of acridine formation with IC50 values of 15.5 and 0.31 microM, respectively. Further analysis indicates mixed non-competitive type inhibition by methadone with inhibition constants (Kis and Kii, respectively) of 0.03 +/- 0.01 (SE) and 0.57 +/- 0.12 microM.
Subject(s)
Aldehyde Oxidoreductases/antagonists & inhibitors , Liver/drug effects , Methadone/pharmacology , Acridines/analysis , Acridines/metabolism , Acridones , Aldehyde Oxidase , Animals , Dextropropoxyphene/pharmacology , Liver/enzymology , Proadifen/pharmacology , RatsABSTRACT
A series of 4-substituted aniline mustards ArNH(CH2)nOpC6H4N(CH2CH2Cl)2, where Ar is an acridine and n varies from 2 to 5, interact with DNA. Scatchard analysis shows the compounds bind tightly, with a binding site size similar to that of 9-aminoacridine. The rate of hydrolysis of the mustards, measured by HPLC, is essentially constant across the series. With increasing length of the polymethylene linker, non-covalent binding becomes less strong, but the rate of DNA alkylation increases. Viscometric helix extension measurements and electrophoretic analyses using closed circular supercoiled DNA show that all the compounds are DNA intercalating ligands. Despite these similarities, the compounds are known to have quite different patterns of DNA alkylation, switching from guanine to adenine alkylation as the chain length is extended.
